JPS5959619A - Eye drop - Google Patents

Abstract

PURPOSE:To provide an eye drop administrable without stimulation and pain, exhibiting excellent effect of vitamin C, having excellent pharmacological effect to the eyeball, and useful as a remedy for senile cataract, etc., by using 3-O- glucosyl-L-ascorbic acid as an active component. CONSTITUTION:The objective eye drop contains 3-O-glucosyl-L-ascorbic acid as an active component. 3-O-Glucosyl-L-ascorbic acid is a water-soluble white powder, and can be prepared to the eye drop by dissolving in water by conventional method and adjusting the pH and isotonicity to proper levels. The amount of the 3-O-glucosyl-L-ascorbic acid in the preparation is generally preferably about 0.01-1.0wt%. The active component can be prepared by reacting 5,6-O- isopropylidene-L-ascorbic acid with an acetohalogenated sugar in the presence of a strong organic base such as 4-dimethylaminopyridine in an organic solvent at room temperature, and removing the protecting groups from the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to eye drops, and more particularly to eye drops containing vitamin C as an active ingredient.

Vitamin C (L-ascorbic acid) is a substance that has a variety of medicinal effects including nutritional enrichment effects, and is thought to have excellent pharmacological effects on the eyeballs as well. For example, in vivo, vitamin C is distributed in a relatively large amount in the eyeball, and this is thought to prevent the action of radicals generated by light, which are said to damage the crystalline lens of the eyeball. In addition, vitamin C deficiency can lead to cataracts, and in fact, vitamin C is reduced in cataractous eyes.
The use of vitamin C in the treatment of senile cataracts is thought to be effective not only in replenishing this decrease but also in improving the progression of lens glaucoma. Furthermore, there are reports that combining vitamin C with vitamins A and E lowers intraocular pressure in a short period of time and promotes recovery from glaucoma, and animal studies show that vitamin C prevents corneal ulcers and perforations caused by alkali burns. has been reported. Furthermore, due to the antiviral effect of vitamin C, it is expected to be effective against viral eye diseases.

As described above, vitamin C is expected to exhibit excellent pharmacological effects on the eyeballs, and is therefore considered to be extremely useful as an active ingredient in eye drops. However, there have been no examples of using vitamin C as an active ingredient in eye drops. This is because eye drops are drugs that come into contact with the especially sensitive mucous membranes and cornea of the eye, so they are required to be chemically stable and do not form any precipitates or precipitates, while vitamin C is neutral. This is thought to be due to the fact that it is unstable and unstable in a basic aqueous solution, and cannot meet these requirements.

In recent years, various studies have been conducted to obtain vitamin C derivatives that are extremely stable and can sufficiently exhibit vitamin C activity in vivo, and the present applicant has also developed L-ascorbic acid, which is suitable as such a derivative. 3-0- with 3-position hydroxyl group glucosylated and 4427&wo
We previously filed a patent application for glucosyl-ascorbic acid (Special Patent No. K111, No. 57-080972). after that,
As a result of repeated research, we have found that this derivative satisfies the various properties required for eye drops, including stability, non-irritation, and painlessness.
It has been found that by using this, eye drops that exhibit excellent vitamin C effects can be obtained.

That is, the present invention provides eye drops containing 3-0-glucosyl-ascorbic acid as an active ingredient. ; U-0-glucosyl-ascorbic acid is converted into 5,6-0-impropyritine-■ in an organic solvent in the presence of a strong organic base such as 4-dimethylaminopyridine at room temperature.

- Obtained by reacting ascorbic acid with an acetohalogen sugar such as acetobromglucose, attaching and deprotecting it, it is very stable, and is absorbed by the living body and hydrolyzed into vitamin C and glucose. It is a highly safe, non-irritating, and painless vitamin C derivative that fully exhibits C activity. Therefore, according to the present invention, it is possible to obtain vitamin C-containing eye drops that contain vitamin C in a very stable form and have excellent effects.

Finally, the results of testing the stability of 3-0-glucosyl-ascorbic acid in eye drops are shown.

Eye drop prescription ingredients iV'11fJ, %; 3-0-glucosyl-mono-ascorbic acid 010e-menthol 0.01 boric acid 1.85 borax
0.08 purified water
The remainder: 3-o-glucosyl-L-ascorbic acid combination eye drops were prepared according to the conventional method and left at 40°C. However, ascorbic acid has a constant MtL. One company is high performance liquid chromatography [Shima r
1! Seisakusho I, c-2, Nucleosil 10μ (4nn
x 20 ant] 18 columns, flow rate, 1.0πt/min, eluent: 10 full MKl121'04 (ptl 4.
01)-acetonitrile (95:5), detection wavelength:
245 and 254 on,',l. The residual rate (%) of 3-0-glucosyl-1,-ascorbic acid was calculated from this quantitative value, and its change over time was observed. Similarly, eye drops (control eye drops) were prepared using 3-0-curcosyl-1-mono-ascorbic acid and sodium 15-ascorbate (7). Changes in the residual rate over time were investigated.

The results are shown in the attached Figure 1. Figure 1 is a graph showing the change in residual>S over time, with the vertical axis representing the residual rate and the horizontal axis representing the number of days over time. Line 2 shows the case of control eye drops.

It is clear from this result that 3-0-glucosyl-L
-Ascorbic acid is extremely stable even when left at 40°C for 1.4 r1.

Specifically, 3-0-glucosyl-L-ascorbic acid is a water-soluble white powder, and the eye drops of the present invention are prepared by dissolving the powder in water according to a conventional method and adjusting the pfl and isotonicity as appropriate. This is an alternative to the conventional liquid dosage form. The amount of 3-0-glucosyl-ascorbic acid to be blended can be appropriately selected depending on the desired effect, but is generally preferably about 0.01 to 1.0%.

In addition, if desired, vitamin B 6, vitamin 12,
It may be used in combination with medicinal ingredients such as panthenol, naphazoline hydrochloride, zinc sulfate, maleic chlorpheniramine, sodium chondroitin sulfate, allantoin, cyclocalcium glycyrrhizinate, camphor, geraniol,
Flavor ingredients such as Hatsukaura and e-menthol are also effective in providing a refreshing feeling, and can be incorporated in an amount of 0.005 to 0.1% by weight. In addition, preservative components such as pensalkonium chloride and chlorhequin singleconate parabens, solubilizing agents such as polyhydric alcohol nonionic surfactants, and high Molecular components, isotonic agents such as sodium chloride, potassium chloride, etc. can be appropriately blended.

At the same time, the present invention will be explained in more detail with reference to reference examples and examples.

Reference Example 3-Production of 0-1'' lucosyl-monoscorbic acid 5.6-0-Impropylidene-■,-ascorbic acid 0.53 g (2,46 mm!1 mol) was dissolved in 6 ml of dimedyl sulfoxide. , dimedylaminopyridine 0, :l
(2,46-:!J mol) and stir. To this was added 1 mol of acetofuromor [alpha]-D-curcose], 012,43 mmol), and the mixture was stirred at room temperature (25°C). 1 o'clock I
After Fl, add 300 ml of benzene to the reaction mixture, add 100 ml of water, and then add 1.00 ml of saturated saline.
Wash 3 times with l. The benzene layer is dried and evaporated under reduced pressure to obtain a white foam. These substances o and sy were purified by silica gel column chromatography (silica gel 257.
1.2 (AX 50 Cm column) and eluted with benzene-ethyl acetate (]:1) to give a clear oily 5.
6-0-Improviridene: 3-0- (2,3,4
,6-Citler O-acetylglucopyranosyl)-L-
Obtain ascorbic acid. This is reduced to 1 in the desiccator.
・Crystallizes when irradiated to .

Melting point: 163-166°C 1R: 1719, 1772 C-1Uv: λmax
238. □ nm [α month]: +9° (C=1.0, cncg; 3)
The obtained 5,6-0-impropyritin-3-0-(2
, 3,4,6-tetra-0-acetylglucopyranone)-1-ascorbic acid 0. : 3 g (0.55 mmol) was dissolved in 6 ml of methanol, and a 55% potassium carbonate solution [potassium carbonate 0.33! Prepared by dissolving (2,39 mmol) in 6 yrtl of water, add 2j and stir at room temperature (
Leave at 25°C. After 45 minutes, the reaction mixture is neutralized to pH 7 by treatment with Amberlite tR-t2o (11+ form). The reaction mixture was filtered and evaporated under reduced pressure to obtain 0.3 g of a white foamy substance, which was purified by silica gel column chromatography (
The mixture was applied to silica gel (15) and eluted with tetraroform-methanol (3:2) to obtain white crystalline 3-0-curcosyl-mono-ascorhinic acid.

U■:λmax 24. Q, Q nm iogε-
, -3,61 (methanol) Example 1 Eye drops were prepared by a conventional method according to the following prescription (also.

J Ebisu Min City f74% Propylene Glycol 0.50 Chlorobutanol ()01 Disatonium Hydrogen Phosphate 0.01 Boric Acid
1.30 Sodium chloride Isotonic with lacrimal fluid 1u-3-〇-glucosyl-ascorbic acid 0. ],
0 Purified water Remainder The eye irritation of this eye drop was evaluated by a panel of 20 people, and no irritation was observed at all.

Example 2 Eye drops were prepared in a conventional manner according to the following recipe.

Ingredient Weight L Vitamin 1312 0.0
14-Menthol 0.0
13-0-Glucosyl-ascorbic acid 0.30 Benzalkonium chloride 0.01 Ho w1
．． 15 Borax 0.10 Purified water Remainder Example 3 Prepare eye drops according to the prescribed recipe using a conventional method.

Ingredients: [1; 1%; 3-0-glucosyl-L-ascorbic acid 0.10 Potassium chloride 1.00 Sodium hydrogen carbonate 03゜Purified water
Remainder +'+iJ Example 1
The effectiveness of the eye drops was tested as described above.

(1) Effect on corneal wounds in rabbit eyes A disc-shaped defect with a diameter of 5# reaching the center of the corneal stroma was created in the center of both corneas of a mature white rabbit, and the progress of the defect was observed.

For the left eye, 3-0-curkonoru 1 of Example 1 was applied. - Ascorbic acid-containing eye drops were instilled into the eyes 1115 times, and 09% saline was instilled into the right eye as a control.

The examination consisted of magnified observation using a 1111 slit-lamp keratoscope, a fluorescein staining test, and a comparison between the left and right eyes through observation and photography of the slit-lamp cross section.

Although the -1-dermal development of the left eye was delayed compared to the control eye (right eye), the growth of the parenchyma was better, and parenchymal regeneration was more pronounced in the left eye. On the other hand, in the right eye, there is a -1-skin of 71" from the first mouth, but the surface is phase Jl, 7+7, the parenchyma is poor, and the thickness of the corner of the left eye is 11/j. A clear difference was observed compared to .

From this result, the eye drops containing 3-O-curcon-L-ascorbin 1 cane are clearly effective against corneal wounds.

(2) Usage test for eye strain Case 1: 40 years old, female, row 1 worker For about a month now, I have been experiencing binocularity and visual disturbances when working nearby.

Visual crab R, V, = Q, 5 (1, Q m1t-1,
Q I) ), L, V= Q, 5 (1,2m1t −
1, Q l)) There are no abnormalities in the anterior segment, intermediate lucidum, or fundus. Both left and right by continuous periapsis measurement] 5 C〃l→2
Q: It was extended to CM. By instilling the 3-0-curcosyl-, -ascorbin) compound eye drops in Example 1, 1
After a week, the main complaint had almost disappeared and had become effective.

Case 2: A 21-year-old male student who sometimes experiences bloodshot eyes, especially when reading. Binocular conjunctival hyperemia and tenderness in the main orbit continued. There were no abnormalities in the anterior segment or the intermediate lucid body, and the ocular IU was normally extended from 12 CIJr to 20 cm using continuous near point measurements. Example 10)
After 4 weeks, eye drops containing 3-0-glucosyl-L-ascorbic acid were effective in reducing hyperemia and fatigue during near work.

[Brief explanation of drawings]

FIG. 1 is a graph showing the results of a stability test of 3-0-glucosyl-L-ascorbic acid in eye drops. Special applicant: Zanstar Co., Ltd. Agent: Patent attorney Aoyama Aoyama and 2 others Figure 1

Claims (1)

[Claims] (1) An eye drop containing 3-0-curcosyl-1-ascorbic acid as an active ingredient.